Alzheimer's disease (AD) is a genetically and phenotypically heterogeneous disorder due to multiple etiologies that is operationally defined as a progressive dementia with abundant Abeta-rich senile plaques (SPs) and tau-rich neurofibrillary tangles (NFTs) in the brains of affected patients, but more than 50% of AD patients also show Lewy bodies (LBs) formed by alpha-synuclein. Although most AD is sporadic, gaps in understanding non-genetic contributions to AD limit efforts to delay its onset/course by minimizing environmental AD risk factors. Significantly, we recently reported the first experimental data in a transgenic (TG) mouse model of AD-like Abeta amyloidosis (Tg2576 or APPswe) linking traumatic brain injury (TBI) to accumulations of Abeta and oxidative stress using a novel mild repetitive TBI (mrTBI) paradigm. Thus, we hypothesize that TBI augments formation of AD SPs, NFTs and possibly LBs by increasing oxidative stress and predisposing individuals to AD. Based on this and additional progress from the current funding cycle of this Program Project Grant (PPG), we will investigate new TG mouse models of major AD lesions (SPs, NFTs, LBs) to delineate neurodegenerative pathways activated by TBI that lead to an AD-like phenotype. This will include studies of mrTBI in more robust, recently developed, TG mouse models of AD-like Abeta amyloidosis as well as TG mouse models that specifically accumulate deposits of Abeta11-40/42 (which has been underestimated in the pathogenesis of AD), and recently developed TG mouse models of tau and AS inclusions crossed with the Abeta amyloidosis TG mice. Thus, in the Aims proposed here, we will test our hypothesis that TBI increases the risk for developing AD neurodegeneration by increasing oxidative stress and accelerating the formation of SPs, NFTs and LBs in novel TG mouse models.